Eflornithine (DFMO) Prevents Progression of Pancreatic Cancer by Modulating Ornithine Decarboxylase Signaling
| Autor: | Chinthalapally V. Rao, Naveena B. Janakiram, Rebekah L. Ritchie, Vernon E. Steele, Altaf Mohammed, Stan Lightfoot, Laura Biddick, Venkateshwar Madka, Jagan M.R. Patlolla, Misty Brewer, Michael Sadeghi |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Cancer Research medicine.medical_specialty Eflornithine Blotting Western Apoptosis Biology Ornithine Decarboxylase Real-Time Polymerase Chain Reaction medicine.disease_cause Article Ornithine decarboxylase Immunoenzyme Techniques Proto-Oncogene Proteins p21(ras) Mice Pancreatic tumor Internal medicine Pancreatic cancer Tumor Cells Cultured medicine Animals Humans RNA Messenger Cell Proliferation Oncogene Reverse Transcriptase Polymerase Chain Reaction Ornithine Decarboxylase Inhibitors medicine.disease Xenograft Model Antitumor Assays Mice Inbred C57BL Pancreatic Neoplasms medicine.anatomical_structure Endocrinology Oncology Ornithine Decarboxylase Inhibitor Mutation Disease Progression Cancer research Female KRAS Pancreas Carcinoma Pancreatic Ductal Signal Transduction medicine.drug |
| Zdroj: | Cancer Prevention Research. 7:1198-1209 |
| ISSN: | 1940-6215 1940-6207 |
| Popis: | Ornithine decarboxylase (ODC) is the key rate-limiting enzyme in the polyamine synthesis pathway and it is overexpressed in a variety of cancers. We found that polyamine synthesis and modulation of ODC signaling occurs at early stages of pancreatic precursor lesions and increases as the tumor progresses in Kras-activated p48Cre/+-LSL-KrasG12D/+ mice. Interest in use of the ODC inhibitor eflornithine (DFMO) as a cancer chemopreventive agent has increased in recent years since ODC was shown to be transactivated by the c-myc oncogene and to cooperate with the ras oncogene in malignant transformation of epithelial tissues. We tested the effects of DFMO on pancreatic intraepithelial neoplasias (PanIN) and their progression to pancreatic ductal adenocarcinoma (PDAC) in genetically engineered Kras mice. The KrasG12D/+ mice fed DFMO at 0.1% and 0.2% in the diet showed a significant inhibition (P < 0.0001) of PDAC incidence compared with mice fed control diet. Pancreatic tumor weights were decreased by 31% to 43% (P < 0.03–0.001) with both doses of DFMO. DFMO at 0.1% and 0.2% caused a significant suppression (27% and 31%; P < 0.02–0.004) of PanIN 3 lesions (carcinoma in situ). DFMO-treated pancreas exhibited modulated ODC pathway components along with decreased proliferation and increased expression of p21/p27 as compared with pancreatic tissues derived from mice fed control diet. In summary, our preclinical data indicate that DFMO has potential for chemoprevention of pancreatic cancer and should be evaluated in other PDAC models and in combination with other drugs in anticipation of future clinical trials. Cancer Prev Res; 7(12); 1198–209. ©2014 AACR. |
| Databáze: | OpenAIRE |
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